CN110698445B - 3-amine alkyl phthalide compound, preparation method and application thereof - Google Patents
3-amine alkyl phthalide compound, preparation method and application thereof Download PDFInfo
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- CN110698445B CN110698445B CN201810745452.0A CN201810745452A CN110698445B CN 110698445 B CN110698445 B CN 110698445B CN 201810745452 A CN201810745452 A CN 201810745452A CN 110698445 B CN110698445 B CN 110698445B
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- Prior art keywords
- acid
- compound
- pharmaceutically acceptable
- reaction
- aminoalkylphthalide
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical class [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel 3-amine alkyl phthalideThe compound (I) and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicines for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve damage caused by brain trauma and the like;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel 3-amine alkyl phthalide compound (I), a preparation method and a pharmaceutical composition thereof, and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer disease, parkinson disease, huntington disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic cerebral apoplexy, hemorrhagic cerebral apoplexy, nerve injury caused by cerebral trauma and the like.
Background
Alzheimer's Disease (AD) is a central nervous system degenerative disease mainly composed of progressive cognitive impairment and memory impairment, and the incidence of Alzheimer's disease tends to rise year by year, and is a high-incidence disease next to cardiovascular disease and cancer, and has risen to be the fourth cause of death in developed countries such as Europe and America. According to the report of the world health organization, 10% of the aged people over 65 years worldwide have dysnoesia, of which half of them have dementia and the incidence rate over eighty-five years is nearly 50%. The number of AD patients in China is about 600-700 ten thousand, and the incidence rate is more than 5%. With the acceleration of the aging process of the global population, the incidence rate of the disease is in a remarkable rising trend, and the global influence of Alzheimer disease is published in 12 months of 2013 according to Alzheimer's Disease International: 2013-2050 reports indicate that AD will be the biggest health challenge facing the world for the next decades, and by 2030 the number of patients will rise from 4400 ten thousand in 2013 to 7600 ten thousand, and by 2050 this value will reach a striking 1.35 hundred million. AD is manifested by diminished memory, orientation, thinking and judgment, and diminished daily life, even abnormal mental behaviorSymptoms, etc., make patient nursing difficult, bring heavy burden to society and family. Drugs currently approved for the treatment of mild/moderate AD are acetylcholinesterase (AChE) inhibitors, as well as for the treatment of severe ADNMethyl-)DAspartate (NMDA) receptor antagonists, however, clinical use has shown that these drugs can alleviate AD symptoms by increasing acetylcholine levels or inhibiting excitotoxicity of excitatory amino acids in patients, but are not effective in preventing or reversing the course of the disease, and can also cause serious toxic side effects such as hallucinations, confusion, dizziness, headache, nausea, hepatotoxicity, anorexia, and frequent bowel movements, thus providing undesirable long-term efficacy. Thus, there is a great clinical need to develop new therapeutic agents for AD that have both symptomatic improvement and altered course of disease.
The pathogenesis of AD is complex due to various factors, and the pathogenesis of AD is not completely elucidated yet. However, studies have shown that the level of acetylcholine in the brain of the patient is reduced,βExcessive production and deposition of amyloid, platelet aggregation in cerebral vessels, metal ion metabolism disorder, ca 2+ Dysbalance of,tauMany factors, such as neurofibrillary tangles, glutamate receptor hyperactivity, oxidative stress to produce large amounts of Reactive Oxygen Species (ROS) and free radicals, and neuroinflammatory reactions, caused by protein hyperphosphorylation play an important role in the pathogenesis of AD. For the above-mentioned pathogenesis, researchers have adopted the traditional "one drug one target" drug design strategy, and found a large number of drugs with high activity and high selectivity to a certain target, such as: cholinesterase inhibitorsNMethyl-)D-aspartate receptor antagonists and the like. However, the medicines have the problems of single action target point, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.
In recent years, along with the continuous elucidation of the pathogenesis of AD, the occurrence and development of AD are found to have the characteristics of multi-mechanism and multi-factor effect, and the different mechanisms are mutually related and influenced, so that a complex network regulation and control system in the occurrence and development process of AD is formed. Obviously, the development of therapeutic agents that can act simultaneously on multiple links in the pathological process of AD is a current necessary choice. Based on the above resultsResearchers have proposed a "Multitarget-directed Ligands" (MTDLs) strategy to develop anti-neurodegenerative drugs. By "multi-target ligand" is meant that a single chemical entity acts on multiple targets in the disease network simultaneously, and the action on each target can produce a synergistic effect such that the total effect is greater than the sum of the individual effects, such compounds are also known as "multi" or "multi" agents. The main differences of the multi-target medicine and multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between medicines, and have the advantages of toxic and side effects, uniform pharmacokinetics, convenient use, etc. Therefore, research and development of the anti-neurodegenerative disease treatment drug with novel chemical structure, novel action mechanism, multi-target effect and low toxic and side effect not only meets the urgent requirements of the aging process of society, but also has good market prospect. A large number of clinical studies have demonstrated that AChE inhibitors are effective in alleviating symptoms in AD patients with positive short-term therapeutic efficacy; therefore, it is generally necessary to retain the AChE inhibitory activity of the compound (inhibiting the enzyme is essential for improving the symptoms of AD patients) and add one or more other targets or functions with pharmacological synergism on the basis of the AChE inhibitory activity to achieve the multi-target AD therapeutic effect [ 1, huang Shufang, etc. ] research progress of multi-target Alzheimer's disease therapeutic drugs; 2. luo Wen the research progress of multi-target small molecule inhibitors for treating Alzheimer's disease, journal of Chinese medicinal chemistry 2011, 21 (6): 442-443 ]. Obviously, the design and the discovery have the functions of inhibiting acetylcholinesterase and inhibiting acetylcholinesteraseβMulti-target therapeutic agents against amyloid overproduction and deposition, antioxidant stress, anti-platelet aggregation, and anti-neuroinflammatory reactions remain currently important directions of research.
Disclosure of Invention
The invention aims to disclose a 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims at disclosing a preparation method of the 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salts thereof;
it is a further object of the present invention to disclose pharmaceutical compositions comprising such 3-aminoalkylphthalides (I) and pharmaceutically acceptable salts thereof;
it is still another object of the present invention to disclose the use of the 3-aminoalkylphthalides and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of neurological related disorders, including, but not limited to, vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and brain trauma induced nerve damage.
The chemical structural general formula of the 3-amine alkyl phthalide compound (I) provided by the invention is as follows:
wherein: x represents O, NR 7 Or S; a is that 1 -A 2 Represents CH-CH 2 Or c=ch; when A is 1 -A 2 When c=ch, the compound isZ-a configuration,E-configuration, orZ-form of a lens andE-any ratio mixture of the formula configuration; when A is 1 -A 2 Represents CH-CH 2 In the case of the compounds described areRConfiguration(s),SConfiguration, orRConfiguration and method of useSMixtures of any ratio of configurations; n represents 1 to 12; r is R 3 And R is 4 Each independently represents H, OH, SH, C 1 ~C 12 Alkyl, C 1 ~C 12 Alkoxy, CN, halogen, NR 5 R 6 Or C 1 ~C 12 Alkylthio; r is R 5 And R is 6 Each independently represents H, C 1 ~C 12 An alkyl group; NR (NR) 5 R 6 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r is R 1 Representation H, C 1 ~C 12 An alkyl group; r is R 2 Represent C 1 ~C 12 Alkyl groupBenzyl or substituted benzyl; NR (NR) 1 R 2 Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, C-substituted at the 4-position 1 ~C 12 Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl at the 4-position, piperazinyl, C at the 4-position 1 ~C 12 Piperazinyl substituted by alkyl, piperazinyl substituted by benzyl or substituted benzyl at the 4-position; r is R 7 Representation H, C 1 ~C 12 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; the term "halogen" refers to F, cl, br, or I; "substituted phenyl" or "substituted benzyl" refers to a benzyl group on the phenyl ring substituted with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 Alkyl, C 1-4 Alkoxy, NR 8 R 9 Trifluoromethyl, trifluoromethoxy, nitro, carboxyl, hydroxyl, cyano, R 8 And R is 9 Each independently represents H or C 1 ~C 12 Alkyl, NR 8 R 9 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; these substituents may be at any possible position of the benzene ring. However, the 3-amine alkyl phthalide compound (I) provided by the invention does not comprise the following compounds:
the 3-amine alkyl phthalide compound (I) provided by the invention can be prepared by the following method:
reacting the corresponding 3-bromide (1) with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2); the obtained compound 2 and an aminoalkylaldehyde compound (3) are subjected to Wittig reaction under proper solvent and alkaline conditions to obtain a corresponding compound (4)E/ZConfigurational mixture (i.eE/ZCompound I mixture of configuration); the mixture of the compound (4) can be separated and purified by silica gel column chromatography by a conventional method to obtain the corresponding compounds respectivelyE-orZ-a compound of formula (la); the obtained mixture of the compound (4) can also be directly hydrogenated in a proper solvent to further reduce double bonds without separation and purificationOriginal, obtain the corresponding raceme of 3-amine alkyl phthalide compound (I); separating the racemate of the corresponding 3-amine alkyl phthalide compound (I) by using a conventional chiral chromatography to obtain the corresponding optical isomer; the reaction formula is as follows:
wherein: x, R 1 、R 2 、R 3 、R 4 And n is defined as the chemical structural general formula of the 3-amine alkyl phthalide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
step A): reacting the 3-bromide (1) with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2); wherein, the solvent used in the reaction is: c (C) 3-8 Aliphatic ketone,N,NDimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C 5-8 Alkanes, preferably solvents are 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, or 1, 4-dioxane; 3-bromide (1): the molar feed ratio of triphenylphosphine was 1.0: 1.0-10.0, preferably a molar feed ratio of 1.0:1.0 to 5.0; the reaction temperature is 40-150 ℃, and the preferable reaction temperature is 60-120 ℃; the reaction time is 1 to 120 hours, preferably 2 to 72 hours.
Step B): the 3-triphenylphosphine salt compound (2) obtained in the step A) and the aminoalkyl aldehyde compound (3) are reacted under proper solvent and alkaline condition to obtain the corresponding compound (4)E/ZA configurational mixture; wherein, the solvent used in the reaction is: c (C) 1-8 Fatty alcohols, C 3-8 Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C 5-8 Alkanes, preferably solvents are: chloroform, dichloromethane, acetone, acetonitrile, tetrahydrofuran or toluene; the alkali used in the reaction is as follows:alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, C 1-8 Alkali metal salts of alcohols, organic tertiary amines or quaternary ammonium bases (e.g. triethylamine, tributylamine, trioctylamine, pyridine,N-methylmorpholine,NMethylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), preferably the base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; compound (2): compound (3): the molar feed ratio of the alkali is 1.0:1.0 to 10.0: 1.0-10.0, preferably a molar feed ratio of 1.0:1.0 to 3.0:1.0 to 5.0; the reaction temperature is 0-120 ℃, and the preferable reaction temperature is room temperature-100 ℃; the reaction time is 20 minutes to 48 hours, preferably 1 to 24 hours.
Step C): directly reducing double bonds in a proper solvent through catalytic hydrogenation without separating and purifying the mixture of the compound (4) obtained in the step B) to obtain a corresponding racemate of the 3-amine alkyl phthalide compound (I); wherein, the solvent used in the reaction is: c (C) 1-6 Fatty alcohols, C 3-8 Aliphatic ketones, C 1-6 Fatty acids, C 1-6 Fatty acid and C 1-6 Esters of fatty alcohols, ethers (e.g., diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, etc.), benzene, toluene or xylene, aliphatic hydrocarbons (e.g., hexane, heptane, octane, etc.), preferred solvents are: tetrahydrofuran, methanol, ethanol or isopropanol; the catalysts used for catalytic hydrogenation are: raney Ni, ptO 2 、1%~30%Pd-C、1%~30% Pd(OH) 2 -C, preferably the catalyst is: raney Ni, ptO 2 5% -20% Pd-C; the mass ratio of the compound (4) to the catalyst is 1.0:0.01 to 1.0; the reaction pressure is normal pressure to 10.0MPa, preferably normal pressure to 2.0 MPa; the reaction temperature is room temperature-150 ℃, preferably room temperature-80 ℃; the reaction time is 1 to 96 hours, preferably 2 to 50 hours.
The 3-aminoalkylphthalide compound (I) obtained according to the above method contains amino group in the molecule, the amino group is basic, and the pharmaceutically acceptable salt can be prepared with any suitable acid by a pharmaceutically conventional salification method, wherein the acid is: saltAcid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Fatty carboxylic acids (e.g. formic acid, acetic acid, propionic acid, etc.), trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Alkylsulfonic acids (e.g., methylsulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 1, 4-butanesulfonic acid.
The starting materials of the present invention, 3-bromo (1) and aminoalkyl aldehyde (3), can be prepared using techniques common in the art, including, but not limited to, the methods disclosed in the following documents: 1. guilong Z.et al. WO 2011130478A1；2、Sakamoto F. et al.Chem. Pharm. Bull.1983, 31(8), 2698-2707；3、Chunzhi Z. et al.Chinese Journal of Organic Chemistry2014, 34, 1881-1888；4、Sugimoto H. et al. US 5100901；5、Mingyu W. et al.European Journal of Medicinal Chemistry2016, 121, 864-879。
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more 3-aminoalkylphthalides (I) or a pharmaceutically acceptable salt thereof, which may further comprise one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that causes a biological or medical response to a tissue, system or animal targeted by a researcher or doctor; the term "composition" refers to a product formed by mixing more than one substance or component; the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances that carry or transport a chemical substance. The ideal proportion of the pharmaceutical composition provided by the invention is that the 3-amine alkyl phthalide compound (I) or pharmaceutically acceptable salt thereof is taken as an active ingredient to account for 2 to 99.5 percent of the total weight.
The 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening:
(1) Inhibitory Activity of 3-Aminoalkylphthalide Compounds (I) against acetylcholinesterase and butyrylcholinesterase
1.0 mmol/L of thiocholine iodide or thiobutyrylcholine iodide (all purchased from Sigma Co.) 30. Mu.L of PBS buffer solution with pH7.4, 20. Mu.L of compound solution to be tested (DMSO content less than 1%) and 10. Mu.L of acetylcholinesterase (rat brain cortex 5% homogenized supernatant, pH7.4 phosphate buffer solution as homogenized medium) or butyrylcholine esterase (rat serum 25% supernatant, pH7.4 phosphate buffer solution as homogenized medium) are sequentially added into a 96-well plate, after the addition and homogenization, incubation is carried out for 15min at 37 ℃, 0.2% of 5,5' -dithio-bis (2-nitrobenzoic acid) (DTNB, purchased from Sigma Co.) solution is added into each well, 30. Mu.L of color development is carried out, the optical density (OD value) of each well at 405nm is measured by an enzyme marker, and the inhibition rate (%) of the compound to enzyme (enzyme inhibition rate (%) = (1-sample group OD value/blank group OD value) ×100% is calculated compared with blank wells without adding a sample to be tested; selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, and obtaining the molar concentration of the compound which is the IC of the compound when the 50% inhibition rate is obtained by linear regression of the negative logarithm of the molar concentration of the compound and the inhibition rate of the enzyme 50 . The measurement results show that the 3-amine alkyl phthalide compound (I) disclosed in the examples of the invention [ comprises: compound (4)E-form of a lens andZthe target substance with the-configuration has obvious inhibition effect on acetylcholinesterase, and IC thereof 50 Is 1.2X10 -3 nM to 20.0 [ mu ] M. Further analysis of structure-activity relationship shows that under the condition of a certain carbon chain length, 3-amine alkyl phthalide compound (I) moleculesEA kind of electronic deviceZThe inhibitory activity of the configuration of the formula is less different from that of acetylcholinesterase, but the inhibitory activity of the configuration of the formula is reduced after double bonds in molecules are reduced; in addition, the chiral configuration of the target has a certain effect on the activity of inhibiting acetylcholinesterase, but they still have significant acetylcholinesterase inhibiting activity, IC thereof 50 Are all smaller than 20.0 mu M. The measurement result also shows that the inhibition activity of the 3-amine alkyl phthalide compound (I) to acetylcholinesterase is obviously higher than that to butyrylThe inhibition activity (selectivity is more than 100 times) of cholinesterase shows that the compound disclosed by the invention has a selective inhibition effect on acetylcholinesterase, and shows that the compound has low toxicity to a peripheral system. In addition, the measurement results also show that the clinically used rivastigmine inhibits the AChE IC 50 IC for butyrylcholinesterase inhibition at 10.5. Mu.M 50 2.6 mu M; and the control compound (II) (wherein Y in the chemical structural formula represents O, NH or S, respectively) and the control compound (III) shown below are ICs for inhibition of acetylcholinesterase 50 Are all larger than 150 mu M;
(2) 3-aminoalkylphthalides (I) to Aβ 1-42 Inhibition of self-aggregation
Reference (Qiang, X.M).et al.Eur. J Med. Chem.2014, 76, 314-331), i.e.: pretreated Aβ 1-42 Stock solutions were made up with DMSO and diluted to 50 μm with PBS buffer ph7.4 prior to use; the test compound was prepared as a stock solution of 2.5. 2.5 mM in DMSO, diluted to the corresponding concentration in PBS buffer pH7.4 before use, and 20. Mu.L of A was takenβ 1-42 Solution +20. Mu.L of test compound solution, 20. Mu.L of Aβ 1-42 Solution +20. Mu.L of PBS buffer (containing 2% DMSO) was incubated in 96-well plates at 37℃for 24h, then 160. Mu.L of 50mM glycine-NaOH buffer (pH=8.5) containing 5. Mu.M thioflavin T was added, and immediately after shaking for 5s, the fluorescence value was determined with a multifunctional microplate reader at 446 nm excitation wavelength and 490 nm emission wavelength; a is thatβ 1-42 The fluorescence value of the +test compound is recorded as IF i ，Aβ 1-42 Fluorescence values of +PBS buffer were recorded as IF c The fluorescence value of the buffer containing PBS alone was recorded as IF 0 Compounds inhibit Aβ 1-42 The inhibition rate of self aggregation is as follows: 100- (IF) i -IF 0 )/(IF c -IF 0 ) 100; selecting five to six concentrations of the compound and determining the inhibition thereof; each concentration of each compoundRepeating the measurement three times, and taking curcumin as a positive control. The measurement results show that the 3-amine alkyl phthalide compound (I) disclosed in the examples of the invention [ comprises: compound (4)EA kind of electronic deviceZPair Aβ 1-42 Self-aggregation has obvious inhibition activity on A at the concentration of 25.0 mu Mβ 1-42 The inhibition rate of self aggregation is between 20.0% and 55.0%; and the anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, the above control compound (II) (wherein Y in the chemical formula represents O, NH or S, respectively) and the control compound (III) correspond to a at a concentration of 25.0 μmβ 1-42 The inhibition rate of self aggregation is less than 10 percent.
(3) Antiplatelet aggregation activity of 3-aminoalkylphthalides (I)
Taking 3 male rabbits, carrying out local anesthesia by using lidocaine, separating the common carotid artery by operation to obtain blood, and taking 3.8 percent sodium citrate 1:9 anticoagulation, centrifugation at 500 r/min for 10 min to prepare Platelet Rich Plasma (PRP), centrifugation of the remainder at 3000 r/min to prepare Platelet Poor Plasma (PPP), and nephelometry to perform platelet aggregation experiments. The assay tube was incubated for 5 minutes with 240. Mu.L of PRP and 30. Mu.L of the test agent at various concentrations, and 30. Mu.L of Adenosine Diphosphate (ADP) (final concentration of 10. Mu. Mol/L), 30. Mu.L of thrombin (final concentration of 0.5U/mL) and 30. Mu.L of Arachidonic Acid (AA) (final concentration of 1.0 mmol/L) as inducers, respectively, and the maximum aggregation rate was recorded for 5 minutes. The inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The measurement results show that the 3-amine alkyl phthalide compound (I) disclosed in the examples of the invention [ comprises: compound (4)EA kind of electronic deviceZThe target object with the formula configuration has obvious inhibition effect on platelet aggregation induced by ADP, thrombin and AA, and the inhibition rate of the platelet aggregation is more than 25.0% at the concentration of 50.0 mu M. And the anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, control compound (II) described above (Y in the chemical formula represents O, NH or S, respectively) and control compound (III) are useful for platelet aggregation at the same concentrationThe inhibition ratio of (2) is less than 15.0%.
(4) Inhibitory Activity of 3-Aminoalkylphthalide Compound (I) against neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing 24-h in a cell culture box, changing into 90 mu L of fresh culture solution without serum after cells are attached, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30 min, setting 3 parallel holes of each concentration, and setting a blank control group; then, with or without LPS, the mixture is placed at 37 ℃ and 5% CO 2 The cell culture was continued in a cell incubator for 24h, MTT solution was added, incubated at 37℃for 4h, the supernatant was discarded, 200. Mu. LDMSO solution was added to each well, after 10 min of gentle shaking, OD values were measured at 490 nm with an ELISA reader, the mean of the OD values measured at different concentrations for each sample was calculated, and cell viability was calculated as follows: cell viability (%) = mean OD of dosing group/mean OD of control group x 100%. The test results show that all 3-aminoalkylphthalides (I) [ including: compound (4)EA kind of electronic deviceZNeither the target of the configuration nor LPS showed cytotoxicity at a concentration of not more than 25. Mu.M (inhibition ratio less than<5%）。
(b) Effect of 3-Aminoalkylphthalide (I) on LPS-induced release of NO by BV-2 cells
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing 24-h in a cell culture box, changing into 90 mu L of fresh culture solution without serum after cells are attached, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30 min, setting 3 parallel holes of each concentration, and setting a blank control group; then LPS is added for stimulation, and the mixture is placed at 37 ℃ and 5 percent CO 2 The cell culture was continued in a cell incubator for 24. 24h, the cell culture supernatants from the different treatment groups were taken, an equal volume of Griess reagent I and an equal volume of Griess reagent II were added, reacted at room temperature in the dark for 10 min, and absorbance was measured at 540. 540 nm to detect the NO level in the cell supernatant (specific procedure was performed according to the NO detection kit instructions). Test results tableAll 3-aminoalkylphthalides disclosed in the examples of the present invention (I) [ comprising: compound (4)EA kind of electronic deviceZThe target object of the formula configuration shows strong inhibition effect on BV-2 cell NO generation induced by LPS in the concentration range of 0.5 mu M to 25 mu M (the inhibition rate at the concentration of 2.5 mu M is more than 20.0 percent), and has obvious dose-effect relationship; and their inhibitory activity was significantly enhanced compared to the above control compound (II) (Y in the chemical structural formula represents O, NH or S, respectively) and control compound (III) at the same concentration (n=6,P<0.05 The 3-amine alkyl phthalide compound (I) disclosed in the embodiment of the invention has obvious anti-neuroinflammation activity. The test further found that the chiral center of compound (I) had no significant effect on the anti-neuroinflammatory activity of the compound.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
Example 1 general preparation of Compound (4)
2.0 mmol of the corresponding 3-bromide (1), 2.4 mmol of triphenylphosphine and 20 ml toluene are added into a reaction bottle, and the mixture is heated, refluxed and stirred for reaction for 12 to 24.0 hours (the reaction progress is tracked by TLC); after the reaction is finished, cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake by toluene and petroleum ether in sequence, and drying to obtain the corresponding 3-triphenylphosphine salt compound (2), wherein the yield is 60.0-88.0%, and the chemical structures of the compounds are all treated by 1 H-NMR confirmation;
adding 1.0 mmol of the 3-triphenylphosphine salt compound (2), 1.3 mmol of the aminoalkyl aldehyde compound (3) and 30. 30 ml of dichloromethane into a reaction bottle, uniformly stirring, adding 1.5 mmol of triethylamine, and stirring at room temperature for reaction for 12-24.0 hours (the reaction progress is tracked by TLC); after the reaction, the solvent was distilled off under reduced pressure, 30 mL deionized water was added to the residue, the pH of the reaction solution was adjusted to strongly acidic with 10% aqueous hydrochloric acid, and thenAdjusting pH of the reaction solution to alkalescence with saturated sodium bicarbonate aqueous solution, extracting with 120 mL dichloromethane for three times, mixing the organic layers, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, and collecting residue as compound (4)E/ZConfiguration mixture, yield: 35.6% -85.0%); separating and purifying the obtained mixture by silica gel column chromatography to obtain corresponding productsE-orZCompounds of the formula (I) whose chemical structure is 1 H-NMR and ESI-MS corroborations.
Example 2 3 preparation of Aminoalkylphthalide Compound (I)
Adding 1.0 mmol of the compound (4) mixture prepared according to the method of example 1 and 25. 25 ml of ethanol into a reaction bottle, uniformly stirring, adding 10% Pd/C40 mg, introducing hydrogen for replacement three times, introducing hydrogen at room temperature and normal pressure, stirring for 2.0-24.0 hours (the reaction process is tracked by TLC), removing the solvent by distillation under reduced pressure after the reaction is finished, purifying the residue by silica gel column chromatography (eluent: dichloromethane: methanol=20-30:1 v/v), and obtaining the corresponding 3-amine alkyl phthalide compound (I), wherein the yield is 60.5-92.0%, and the chemical structure of the compound is all that is obtained by 1 H-NMR、 13 C-NMR and ESI-MS corroboration; the purity of the obtained target is more than 97.0% as determined by HPLC. The structure of the target object prepared by the general method is as follows:
note that: r in the table 1 And R is 2 When sharing a single unit, the substituent "-NR" is represented 1 R 2 ”；
Of part of the compounds 1 The H-NMR data are as follows:
1 H NMR (CDCl 3 ): 7.35-7.27 (m, 4H), 7.26-7.24 (m, 2H), 6.96 (s, 1H), 5.46 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.55 (s, 2H), 2.50 (q, J = 7.6 Hz, 2H), 2.49 (t, J = 7.6 Hz, 2H), 2.21 (s,3H), 1.81−1.75 (m, 2H)；
1 H NMR (CDCl 3 ): 7.30 (s, 1H), 7.29-7.26 (m, 5H), 7.21 (s, 1H), 5.71 (t, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.57 (s, 2H), 2.60 (q, J = 8.4 Hz, 2H), 2.57-2.53 (m, 2H), 2.26 (s,3H), 1.84 (t, J = 7.2 Hz, 2H)；
1 H NMR (CDCl 3 ): 7.32-7.25 (m, 6H), 6.80 (s, 1H), 5.37 (dd, J = 3.6, 7.6 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.52 (s, 2H), 2.41 (t, J = 6.8 Hz, 2H), 2.22 (s,3H), 2.04-1.99 (m, 1H), 1.73-1.69 (m, 1H), 1.62-1.58 (m, 2H), 1.54-1.47 (m, 2H)；
1 H NMR (CDCl 3 ): 7.67 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.04 (s, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 5.53 (t, J = 8.0 Hz, 1H), 4.24 (s, 2H), 4.03 (s, 3H), 3.96 (s, 3H), 3.86 (s, 3H), 3.07 (q, J = 8.0 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H) , 2.48 (q, J = 7.2 Hz, 2H), 2.21-2.17 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H);
1 H NMR (CDCl 3 ): 7.46 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.67 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.78 (s, 5H), 2.78-2.70 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 1.98-1.88 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H)；
1 H NMR (CDCl 3 ): 7.44 (d, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 5.35 (dd, J = 3.6, 7.6 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.82 (s, 3H), 3.71 (s, 2H), 2.63 (q, J = 6.8 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.04-1.99 (m, 1H), 1.73-1.64 (m, 3H), 1.56-1.47 (m, 2H), 1.12 (t, J = 6.8 Hz, 3H)；
1 H NMR (CDCl 3 ): 7.24 (s, 1H), 7.02 (s, 1H), 5.52 (t, J = 7.6 Hz, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 2.62-2.55 (m, 6H), 2.49 (q, J = 7.6 Hz, 2H), 1.92-1.85 (m, 2H), 1.75-1.72 (m, 4H), 1.55-1.50 (m, 2H)；
1 H NMR (CDCl 3 ): 7.30 (s, 1H), 7.22 (s, 1H), 5.73 (t, J = 8.0 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 2.59 (q, J = 7.6 Hz, 2H), 2.47 (t, J = 7.2 Hz, 6H), 1.87-1.80 (m, 2H), 1.64-1.60 (m, 4H), 1.48-1.45 (m, 2H)；
1 H NMR (CDCl 3 ): 7.26 (s, 1H), 6.89 (s, 1H), 5.40 (dd, J = 3.2, 8.0 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 2.95-2.90 (m, 4H), 2.78 (t, J = 8.0 Hz, 2H), 2.20-2.12 (m, 1H), 1.95-1.88 (m, 6H), 1.80-1.71 (m, 1H), 1.61-1.45 (m, 4H)。
example 33 salt formation of Aminoalkylphthalide (I) with acid
Adding 1.0 mmol of the 3-amine alkyl phthalide compound (I) and 25. 25 ml of acetone obtained in the embodiment 1 and the embodiment 2 into a reaction bottle, stirring uniformly, adding 2.5 mmol of corresponding acid, heating, refluxing and stirring for reaction for 20 minutes, cooling to room temperature after the reaction is finished, decompressing and evaporating the solvent to obtain the salt of the 3-amine alkyl phthalide compound (I), and separating and purifying by a conventional method to obtain the salt of the 3-amine alkyl phthalide compound (I), wherein the chemical structure of the salt is that 1 H NMR and ESI-MS corroborations.
Claims (8)
1. A3-amine alkyl phthalide compound or pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
wherein: x represents O, NR 7 Or S; a is that 1 -A 2 Represents CH-CH 2 Or c=ch; when A is 1 -A 2 When c=ch, the compound is in the Z-configuration, E-configuration, or any ratio mixture of Z-and E-configurations; n represents 1 to 12; r is R 3 And R is 4 Each independently represents H, OH, methyl, methoxy, chloro, bromo, dimethylamino, tetrahydropyrrolyl, or methylthio; r is R 1 Represents methyl or ethyl; r is R 2 Represents methyl, ethyl, benzyl or substituted benzyl; when NR is 1 R 2 When ring-formed, it represents tetrahydropyrrolyl, morpholinyl, piperidinyl substituted at the 4-position with ethyl or benzyl, piperazinyl substituted at the 4-position with methyl, benzyl or 2-methoxybenzyl; r is R 7 Represents H, methyl or phenyl; the term "substituted benzyl" refers to a benzyl group on the phenyl ring substituted with 1 to 4 groups selected from the group consisting of: F. cl, br, methyl, methoxy, dimethylamino, trifluoromethyl or trifluoromethoxy, which may be in any possible position of the benzene ring; however, the above-mentioned 3-aminoalkylphthalide compound (I) does not include the following compounds:
2. the 3-aminoalkylphthalide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a mixture of the 3-aminoalkylphthalide compound with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Fatty carboxylic acid, trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Salts of alkylsulfonic acid, camphorsulfonic acid, naphthalene sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1, 4-butanesulfonic acid.
3. A process for the preparation of a 3-aminoalkylphthalide compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 2, wherein the compound is obtainable by:
wherein: x, R 1 、R 2 、R 3 、R 4 And n is defined as the chemical structural general formula of the 3-amine alkyl phthalide compound (I);
step A): reacting the corresponding 3-bromide (1) with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2);
step B): the 3-triphenylphosphine salt compound (2) obtained in the step A) reacts with the corresponding aminoalkyl aldehyde compound (3) under the condition of solvent and alkalinity to obtain an E/Z configuration mixture of the corresponding compound (4); the mixture is separated and purified by a conventional method through silica gel column chromatography, and corresponding E-type or Z-type configuration compounds can be obtained respectively;
step C): reducing the double bond of the compound (4) obtained in the step B) in a proper solvent through catalytic hydrogenation to obtain a corresponding raceme of the 3-amine alkyl phthalide compound (I); separating the racemate of the corresponding 3-amine alkyl phthalide compound (I) by using a conventional chiral chromatography to obtain the corresponding optical isomer;
the 3-amine alkyl phthalide compound (I) obtained by the method contains amino, the amino is basic, and pharmaceutically acceptable salts can be prepared by a pharmaceutically conventional salt forming method with any appropriate acid.
4. The method for preparing 3-aminoalkylphthalide compound or pharmaceutically acceptable salt thereof according to claim 3, wherein in step a), the solvent used in the reaction is: c (C) 3-8 Aliphatic ketones, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C 5-8 An alkane; 3-bromide (1): the molar feed ratio of triphenylphosphine was 1.0:1.0 to 10.0; the reaction temperature is 40-150 ℃; the reaction time is 1 to 120 hours.
5. The method for preparing 3-aminoalkylphthalide compound or pharmaceutically acceptable salt thereof according to claim 3, wherein in step B), the solvent used in the reaction is: c (C) 1-8 Fatty alcohols, C 3-8 Aliphatic ketones, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C 5-8 An alkane; the alkali used in the reaction is as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, C 1-8 Alkali metal salts of alcohols, triethylamine, tributylamine, trioctylamine, pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide; compound (2): compound (3): the molar feed ratio of the alkali is 1.0:1.0 to 10.0:1.0 to 10.0; reaction temperatureThe temperature is 0-120 ℃; the reaction time is 20 minutes to 48 hours.
6. The method for preparing 3-aminoalkylphthalide compound or pharmaceutically acceptable salt thereof according to claim 3, wherein in step C), the solvent used in the reaction is: c (C) 1-6 Fatty alcohols, C 3-8 Aliphatic ketones, C 1-6 Fatty acids, C 1-6 Fatty acid and C 1-6 Esters of fatty alcohols, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene or xylene, hexane, heptane, octane; the catalysts used for catalytic hydrogenation are: raney Ni, ptO 2 、1％～30％Pd-C、1％～30％Pd(OH) 2 -C; the mass ratio of the compound (4) to the catalyst is 1.0:0.01 to 1.0; the reaction pressure is normal pressure to 10.0MPa; the reaction temperature is between room temperature and 150 ℃; the reaction time is 1-96 hours.
7. A pharmaceutical composition comprising a 3-aminoalkylphthalide compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
8. Use of a 3-aminoalkylphthalide compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting aβ by an acetylcholinesterase inhibitor 1-42 Use of an agent that self-aggregates, anti-platelet aggregation or anti-neuroinflammation for the treatment and/or prevention of a disease, such as: vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV-associated dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.
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